Antitussive compositions and method with isonipecotic acid derivatives

ABSTRACT

1-PHENYLALKYL-ISONIPECOTIC ACID AMIDES SUBSTITUTED IN 4POSITION BY ALLYL OR PROPINYL AS WELL AS THE PARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF ARE ANTISUSSIVE AGENTS. PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS AND METHODS FOR PRODUCING AN ANTITUSSIVE EFFECT IN MAMMALS COMPRISING ADMINISTERING SUCH COMPOUNDS ARE PROVIDED. AN ILLUSTRATIVE EMBODIMENT IS 1-(3PHENYLPROPYL)-4-ALLYL-ISONIPECOTIC ACID MORPHOLIDE.

"United States Patent 3,737,538 ANTITUSSIVE COMPOSITIONS AND METHOD WITHISONIPECOTIC ACID DERIVATIVES Hans Herbert Kuhnis and Rolf Denss, Basel,Switzerland,

assignors to Ciha-Geigy Corporation, Ardsley, N.Y. No Drawing. Originalapplication Dec. 30, 1968, Ser. No. 788,068, now Patent No. 3,586,678.Divided and this application Oct. 23, 1970, Ser. No. 83,625

Int. Cl. A61k 27/00 U.S. Cl. 424-248 6 Claims ABSTRACT OF THE DISCLOSURE1-phenylalkyl-isonipecotic acid amides substituted in 4- position byallyl or propinyl as well as the pharmaceutically acceptable acidaddition salts thereof are antitussive agents. Pharmaceuticalcompositions containing these compounds and methods for producing anantitussive effeet in mammals comprising administering such compoundsare provided. An illustrative embodiment is 1-(3-phenylpropyl)-4-allyl-isonipecotic acid morpholide.

CROSS-REFERENCE TO RELATED APPLICATION This is a division of Ser. No.788,068, filed Dec. 30, 1968, now U.S. Pat. No. 3,586,678.

DETAILED DESCRIPTION The present invention relates to novell-phenylalkylisonipecotic acid amides which have valuablepharmacological properties, to pharmaceutical compositions and tomethods of producing an antitussive effect.

More in particular, the present invention relates to compounds of theformula R: R2 CO-N R C: CHi

CH CH2 wherein R is phenylalkyl having at most 9 carbon atoms,

R is allyl or propinyl, and

R and R are, independently of each other, hydrogen,

lower alkyl or lower alkenyl, or

R and R are, together with the adjacent nitrogen atom,polymethyleneimino having from 5 to 7 ring members, or morpholino,

R is 3-phenylpropyl, R is allyl or propinyl, R is hydrogen and R ishydrogen, methyl, isopropyl or allyl, or R and R together with theadjacent nitrogen atom is morpholino.

Particularly good antitussive activity exhibit the hydrochlorides ofN-methyl-l-(3-phenylpropyl)-4-allyl-isonipecotamide, N isopropyl1-(3-phenylpropyl)-4-allylisonipecotamide, l(3-phenylpropyl)-4-allyl-isonipecotic acid morpholide andl-(3-phenylpropyl)-4(2-propinyl)- isonipecotic acid morpholide. Thesecompounds are preferred members of the above subclass.

As an example of the use of the compounds of the present invention, theuse of l-(3-phenylpropyl)-4-allylisonipecotic acid morpholidehydrochloride in producing an antitussive effect in cats will bedescribed. The method is that described by R. Domenjoz, Arch. exp. Path.and Pharmakol, 215, 19-24 (1952).

Healthy cats of normal Weight are narcotized by intraperitonealinjection of 30-65 mg./kg. of aprobarbital so that a relativelysuperificial narcosis is obtained. About 45 minutes after the injectionof the narcotic, the preparation of the Nervus laryngeus superior isstarted by fitting on an irritation-electrode. An apparatus manufacturedby Grass Medical Instruments, Type SDS, allowing irritation of theaforesaid nerve with rectangular currentimpulses of any desiredfrequency and intensity is connected to the electrode. Theirritation-frequency applied is 5 cycles at an irritation-intensitybetween 0.5 and 3 volts.

The irritation-duration is about 8 seconds and the interval between twoirritations is about 120 seconds. For the registrations of the coughreflexes, a Marey capsule is used. A respiration-cannula is introducedthrough the oral cavity down to the glottic chinlr. The hydrochloride of1-(3-phenylpropyl)-4-allyl-isonipecotic acid morpholide is injectedintravenously in form of an 0.5% aqueous solution just before theirritation starts. Cough reflexes are inhibited with about 1 mg./kg. ofthe active compound.

Similar results are obtained with other compounds of the invention,particularly with the preferred members of the subclass.

A further method of showing the antitussive activity is to determine themanner in which tussive irritation in guinea pigs caused by sulphurdioxide is stopped as a result of subcutaneous or oral administration ofthe test substances: In a preliminary experiment for selecting animalsfor testing, male guinea pigs are exposed in a plexiglass chamber to aSO CO -air mixture, flowing through at atmospheric pressure, and with aconstant mixture ratio of 20 ml.: 1.5 liters:10.5 liters per minute,until commencement of coughing or for a maximum of 120 secs. Theassessment of the commencement of coughing is made by inspection. Theguinea pigs reacting by coughing (ca. of all animals) are formed intogroups, each containing 6 animals. Ca. 24 hours after the preliminarytest, these groups of experimental animals receive the test substance,administered subcutaneously or perorally, in various dosages suitablefor ascertaining the ED in mg./kg. Exposure to the irritant gas occursin the same manner as in the preliminary test after 30 and after minutesfollowing application of the test substances. Assessment of thecommencement of coughing is again made by inspection. From thepercentage figures, obtained in the case of various dosages, of animalsno longer reacting to S0 the dosage (=ED preventing the occurrence ofcoughing in the case of 50% of the animals is determined by graphicalinterpolation using the Schleicher and Schiill 298 /2 probability graph.

The preferred members of the subclass were found to have an ED of about50 to about 75 mg./kg. on oral administration.

The acute toxicity of the compounds of the invention is of low order asdetermined in mice on intravenous administration.

Of particular advantage is the fact that the compounds of the inventionhave no, or only insignificant analgesic activity. This lack ofanalgesic activity becomes apparent in the test according to the methodof F. Gross, Helvet. Physiol. Acta. 5, C31 (1947), whereby the apparatusof Friebel is used. The apparatus comprises an electrically heated lampwhich is placed in the focus of a semielliptical metal concave mirror.Under the mirror, on a turn-table, there are located small Plexiglasscages, each holding a white mouse in such a position that the mouse-tailrests stretched out in a small groove on a plexiglass plate. Theturn-table can be turned so that the mouse-tails one after the othercome to be placed into the second focus of the elliptical mirror. Painis induced by the convergent heat radiation from the mirror and the timeis measured from the moment when the heat reaches the mouse-tail tillthe moment at which the mouse twitches its tail.

Two series of 10 mice each are tested prior to the administration of thetest compound and the normal reaction time for each mouse is recorded.Then the test compound is administered orally and the reaction timesafter the injection are recorded, thus enabling determination of theintensity and the duration of the analgesic effect of the test compoundadministered.

The preferred members of the compounds of the invention exhibit in thistest during 60 minutes either none or only an insignificant increase ofthe threshold of irritation (prolongation of reaction time) ifadministered intraperitoneally in dosages of about to about 50 mg./kg.

The new piperidine derivatives of the Formula I and theirpharmaceutically acceptable acid addition salts are suitable as activesubstances for pharmaceutical preparations for the treatment of thecough, particularly for relieving and overcoming tussive irritation.Administration can be performed orally, rectally or parenterally.

In the compounds of the Formula I and in the appertaining startingsubstances stated below, R is, e.g. a phenyl alkyl group, such as thebenzyl group, the 2- phenylethyl, or the 3-phenylpropyl group. R and Rare, independent of each other, e.g. hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec. butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, allyl, crotyl, l-methylallyl, Z-methylallyl.Together with the adjacent nitrogen atom, R and R represent, e.g. thel-pyrrolidinyl, piperidino, hexahydro-lH-l-azepinyl, or the morpholinogroup.

To produce the new piperidine derivatives of Formula I and their acidaddition salts, a carboxylic acid of the Formula II CO-OH wherein R andR have the meaning given under Formula I, or a reactive functionalderivative of a such-like carboxylic acid is reacted with a base of theFormula'III wherein R and R have the meaning stated under Formula I orwith a reactive functional derivative or an acid addition salt of thelatter, and the obtained compound of the general Formula I is optionallyconverted into an addition salt with an inorganic or organic acid. Incarrying out this process, for example, an acid of the Formula II isreacted with a base of the Formula III in the presence of acarbodiimide, such as for example dicyclohexyl-carbodiirnide, in aninert solvent, such as, e.g. tetrahydrofuran.

Suitable as reactive functional derivatives of acids of the Formula IIare in particular the halides, and also anhydrides, e.g. the mixedanhydrides with carboxylic acid-semi-esters. These functionalderivatives are reacted with a compound of the Formula III preferably inthe presence of an excess of the reaction components of the Formula IIIin the presence or absence of an inert organic solvent, such as, e.g.methylene chloride, benzene, tetrahydrofuran or dimethyl formamide. Inplace of an excess of a compound of the Formula III, an acid bindingagent, e.g. a strong tertiary organic base, such as triethylamine,pyridin or s-collidine can also be used and optionally can also serve inexcess as a reaction medium.

Activated esters of acids of the Formula II are, e.g. p-nitro-phenylesters and cyanmethyl esters thereof, which are reacted with compoundsof the Formula III in inert organic solvents, if necessary by heating.The l-imidazolide of the stated acids are reacted under similarconditions with compounds of the Formula III.

Also suitable as reactive functional derivatives of acids of the FormulaII are lower alkyl esters and phenyl esters thereof.

As reactive functional derivatives of compounds of the Formula III,which can be reacted direct with acids of the Formula II, mention ismade of the isocyanates and isothiocyanates derived from compounds ofthe Formula III having a hydrogen atom as R The isocyanates andisothiocyanates are heated with the acids of the Formula II, until theequimolar quantity of carbon dioxide and carbon oxysulphide respectivelyis liberated. The reactions with isocyanates and isothiocyanates can becarried out in the presence or absence of an inert organic solvent ofsufficiently high boiling point and boiling range.

In place of isocyanates preliminary stages thereof can also be used. Inaddition, e.g. N-chlorocarbonyl derivatives of compounds of the FormulaIII, wherein neither R nor R signify hydrogen, are reacted with salts,e.g. alkali salts of acids of the Formula II, in the presence or absenceof inert organic solvents, and the reaction mixtures heated, until theequimolar amount of carbon dioxide is liberated from the primarilyformed carboxylic acid-carbamic acid-anhydrides. Likewise from compoundsof the Formula III with a lower alkyl radical as R sulphurousacid-monoalkyl ester-amides and phosphorous acid-o-phenylenediester-amides can be derived, which when reacted with acids of theFormula II in organic solvents, such as, e.g. pyridine, dioxane ordimethyl formamide and benzene, respectively, yield the desired amidesof the Formula I.

According to a second process for producing the new piperidinederivatives of the Formula I and acid addition salts thereof, a compoundof the Formula IV wherein R R and R have the meaning given under FormulaI, is reacted with a reactive ester of a compound of the Formula V R OH(V) wherein R has the meaning given under Formula I, and optionally theobtained compound of the Formula I is converted into an addition saltwith an inorganic or organic acid. The reaction is carried out at roomtemperature or at a moderately elevated temperature in a suitableorganic solvent, such as, e.g. ethanol, acetone, diethyl ketone ordimethyl formamide. If desired, the reaction is accelerated by addingacid-binding agents, such as, e.g. potassium carbonate, and/orcatalysts, such as for example potassium iodide. Suitable as reactiveesters of compounds of the Formula V are, in particular, halogenhydracid esters, such as bromides, chlorides and iodides, and inaddition arene sulphonic acid esters, such as, e.g. p-toluene sulphonicacid esters. The starting materials of the Formula V are for their partnew compounds, the production of which is explained below.

The 1,4-disubstituted isonipecotic acids of the Formula II, require asdirect or indirect starting materials for the first process are obtainedfor example by quaternisation of lower isonicotinic acid alkyl esterswith reactive esters of compounds of the Formula V, by catalytichydration of the quaternary reaction products, i.e. in the presence ofrhodium-aluminum oxide-catalysts, to obtain l-substituted lowerisonipecotic acid alkyl esters and allylation and propinylation,respectively, of the latter in their 4-position, and finally hydrolysis.

The allylation or propinylation is performed by transformation of thel-substituted, lower isonipecotic acid alkyl esters into their alkalimetal compounds and reaction of the latter with reactive esters of allylalcohol or of 2- propin-l-ol, such as e.g., bromides, iodides orchlorides. Suitable as the reaction medium is, for example, a mixture ofabsolute diethyl ether or tetrahydrofuran and 1,2-dimethoxy ethane(ethylene glycol dimethyl ether). The alkali metal compounds of thel-substituted isonipecotic acid alkyl esters are produced in situ fromother suitable organic alkali metal compounds. The triphenylmethyllithium, which is a particularly suitable such-like compound, ispreferably likewise formed in situ from another organic lithiumcompound, such as phenyl lithium, by adding for example a solution oftriphenyl methane in 1,2- dimethoxy ethane to the phenyl lithium, whichis produced in the known manner, present in diethyl ether. Since thetriphenylmethyl lithium produces intensively coloured solutions, itsformation and also its consumption by the subsequently addedl-substituted isonipecotic acid alkyl ester can be easily followed.Triphenylmethyl soidum or triphenylmethyl potassium can also be used,for example, instead of triphenyl lithium. The stages of the process aremostly slightly exothermic and can be carried out at room temperture orat moderately increased temperature. It must be possible, if need be, tocool the reaction mixture, depending on the starting materials and theamounts used. The reactive functional derivatives of the acids of theFormula 11 are produced in the usual manner, acid chlorides, forexample, preferably with the aid of oxalyl chloride. The l-substitutedlower isonipecotic acid alkyl esters occurring in the above reactionsequence as intermediate products, can also be produced, for example, byreacting lower isonipecotic acid alkyl esters with reactive esters ofcompounds of the formula V, analogously to the second process forproducing compounds of the Formula I.

For producing starting materials of the Formula IV for example, lowerisonipecotic acid alkyl esters are reacted with chloroformic acid benzylester to obtain 1-benzyloxycarbonylisonipecotic acid alkyl esters, andin the 4-position of the latter, are introduced the allyl or 2- propinylgroup in a manner analogous to that described above for the productionof lower isonipecotic acid alkyl esters, substituted in the 1-positionby R The reaction products are subjected to a mild alkaline hydrolysis,the formed 1-benzyloxycarbonyl-4-allyl-isonipecotic acid and-4-(2-propinyl)-isonipecotic acid, respectively, are converted intotheir acid chloride, and the latter is reacted, analogously to the firstprocess for producing compounds of the Formula I, with a base of theFormula H1. The 1- benzyloxycarbonyl group is split off from theobtained amide by the action of hydrogen bromide in glacial acetic acidat room temperature. The N-substituted1-benzyloxycarbonyl-4-allyl-isonipectotamies or-4-(2-propinyl)-isonipecotamides occurring in this reaction sequence asthe final intermediate products can be produced for example by reactingcorresponding N-substituted l-methylor 1-benzyl-4-allyl-isonipecotamides or -4'-(2-propinyl)-isonipecotamideswith chloroformic acid benzyl ester.

Optionally, the piperidine derivatives of the Formula I, obtained usingthe processes according to the invention, are subsequently converted inthe usual manner into their addition salts with inorganic and organicacids. For example, a solution of a piperidine derivative of the FormulaI in an organic solvent, such as diethyl ether, methanol or ethanol, ismixed with the acid desired as the salt component, or a solutionthereof. The salt, which has precipitated immediately or after additionof a second organic liquid, such as, e.g. diethyl ether to methanol, isthen separated.

For use as active substances for medicaments, pharmaceuticallyacceptable acid addition salts can be used instead of free bases, i.e.salts with those acids, the anions of which in the case of the dosagesconcerned exhibit either no pharmacological action or which themselveshave a desired pharmacological action. Moreover, it is of advantage, ifthe salts to be used as active substances crystallise well and are notor only slightly hygroscopic. Hydrochloric acid, hydrobromic acid,sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, ,B-hydroxyethane sulphonic acid, acetic acid, malic acid,tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelicacid, embonic acid, cyclohexylaminosulphonic acid or 1,5-naphthalenedisulphonic acid, for example, can be used for salt formation withpiperidine derivatives of the Formula I.

The new piperidine derivatives of the Formula I and their salts areadministered orally, rectally or parenterally. The daily dosages of freebases or of pharmaceutically acceptable salts thereof vary between 0.1and 3 mg./kg. for adult mammals. Suitable dosage units, such as drages(sugar coated tablets), capsules, tablets, suppositories or ampoules,preferably contain 1-100 mg. of a piperidine derivative of the Formula Ior of a pharmaceutically acceptable salt thereof.

Dosage units for oral application contain as active substance preferablybetween l% and of a piperidine derivative of the Formula I or of apharmaceutically acceptable salt thereof. They are produced by combiningthe active substance with e.g. solid, pulverulent carriers, such aslactose, sucrose, sorbitol, mannitol; starches such as potato starch,maize starch or amylopectin, also laminaria powder or citrus pulppowder; cellulose derivatives or gelatine, optionally with the additionof lubricants, such as magnesium or calcium stearate or polyethyleneglycols, to form tablets or drage cores. The latter are coated, e.g.with concentrated sugar solutions which can also contain, e.g. gumarabic, talcum and/or titanium dioxide, or with a lacquer dissolved ineasily volatile organic solvents or mixtures of solvents. Dyestuffs canbe added to these coatings, e.g. to distinguish between varying dosagesof active substance. Other suitable dosage units for oral administrationare hard gelatine capsules and also soft, closed capsules made ofgelatine and a softener such as glycerine. The former preferably containthe active substance as a granulate in admixture with lubricants such astalcum and magnesium stearate, and optionally stabilisers such as sodiummetabisulphite or ascorbic acid. In soft capsules, the active substanceis preferably dissolved or suspended in suitable liquids such as liquidpolyethylene glycols, whereby likewise stabilisers can be added.

In addition, for the treatment of coughs, lozenges and also multi-dosageoral forms of administration, such as, e.g. cough syrups or cough dropsprepared with the usual auxiliaries, are suitable.

Dosage units for rectal administration are, e.g., suppositories whichconsist of a combination of a piperidine derivative of the Formula I ora suitable salt thereof with a neutral fatty foundation, or alsogelatine rectal capsules which contain a combination of the activesubstance with polyethylene glycols.

Ampoules for parenteral, particularly intramuscular administration, andalso intravenous administration, preferably contain a water-soluble saltof a piperidine derivative of the Formula I as active substance in aconcentration of preferably 0.5-%, optionally together with suitablestabilisers and 'buffer substances, in aqueous solution.

The following prescriptions further illustrate the production of formsof application according to the invention:

(a) g. of active substance, e.g. 1-(3-phenylpropyl)- 4-allyl-N-isopropylisonipecotamide hydrochloride, 30 g. of lactose and 5 g. of highlydispersed silicic acid are mixed. The mixture is moistened with asolution of 5 g. of gelatine and 7.5 g. of glycerin in distilled waterand granulated through a sieve. The granulate is dried, sieved andcarefully mixed with 3.5 g. of potato starch, 3.5 g. of talcum and 0.5g. of magnesium stearate. From the mixture are pressed out 1000 tablets,each weighing 65 mg. and containing 10 mg. of active substance.

(b) 5 g. of active substance, e.g. 1-(3-phenylpropyl)- 4-allylisonipecotic acid morpholide hydrochloride, g. of lactose and g. ofstarch are mixed. The mixture is moistened with a solution of 5 g. ofgelatine and 7.5 g. of glycerin in distilled Water and granulatedthrough a sieve. The granulate is dried, sieved and carefully mixed with3.5 g. of talcum and 0.5 g. of magnesium stearate. 1000 drage cores arepressed out from the mixture. These are then coated with a concentratedsyrup made from 26.66 g. of crystallised sucrose, 17.5 g. of talcum, 1g. of shellac, 3.75 g. of gum arabic, l g. of highly dispersed silicicacid and 0.090 g. of dyestulf and then dried. The obtained drages weigh110 mg. each and each contain 5 mg. of active substance.

(c) To produce 1000 capsules each containing 10 mg. and mg.respectively, of active substance, 10 g. and 25 g. respectively of1-(3-phenylpropyl)-4-allyl-N-methyl isonipecotamide hydrochloride aremixed with 263 g. and 248 g. respectively, of lactose. The mixture ismoistened uniformly with an aqueous solution of 2 g. of gelatine and isgranulated through a suitable sieve (e.g. Sieve III according toPh.Helv. V). The granulate is mixed with 10 g. of dried maize starch and15 g. of talcum and is then evenly filled into 1000 hard gelatinecapsules, size 1.

(d) To prepare a cough syrup containing 0.5% of active substance, 1.5litres of glycerin, 42 g. of p-hydroxybenzoic acid methyl ester, 18 g.of p-hydroxybenzoic acid n-propyl ester and, while slightly warming, 50g. of 1-(3- phenylpropyl) -4-allyl isonipecotic acid morpholidehydrochloride are dissolved in 3 litres of distilled water. 4 litres of70% sorbitol solution, 1000 g. of crystallised sucrose, 350 g. ofglucose and a flavouring, e.g. 250 g. of Orange Peel Soluble Fluidproduced by Eli Lilly and Co., Indianapolis, or 5 g. of'natural lemonfiavouring and 5 g. of Halb and Halb essence, both produced by Haarmannand Reimer, Holzminden, Germany, are added. The obtained solution isfiltered and the filtrate is made up to 10 litres with distilled Water.

(e) A cough syrup containing 0.25% of active substance is produced asfollows: 25 g. of 1-(3-phenylpropyl)-4-allyl-isonipecotic acidmorpholide hydrochloride are dissolved while warming in a mixture of 2.5litres of water and 0.5 litre of ethanol (96%). In addition, a syrup isboiled consisting of 30 litres of water, 1 litre of 70% sorbitolsolution, 3000 g. of crystallised sucrose, 42 g. of p-hydroxybenzoicacid methyl ester and 18 g. of p-hydroxybenzoic acid n-propyl ester, andthe syrup is carefully mixed with the solution of active substance.After the addition of flavourings, e.g. those stated under ((1) and, ifnecessary, filtration, the obtained syrup is made up to 10 litres withdistilled water.

(f) To prepare cough drops containing 2.5% of active substance, 250 g.of 1-(3-phenylpropyl)-4-allyl isonipecotic acid morpholide hydrochlorideand 30 g. of sodium cyclamate are dissolved in a mixture of 4 litres ofethanol (96%) and 1 litre of propylene glycol. In addition, 3.5 litresof 70% sorbitol solution are mixed with 1 litre of water and the mixtureis added to the above solution of active substance. A flavouring, e.g. 5g. of coughdrop aroma or 30 g. of grapefruit essence, both produced byHaarmann and Reimer, Holzminden, Germany, is added and the Whole is wellmixed, filtered and made up to 10 litres with distilled water.

(g) A suppository mixture is prepared consisting of 2.5 g. ofl-(3-phenylpropyl)-4-ally1isonipecotic acid morpholide hydrochloride and167.5 g. of Adeps solidus and with this mixture 100 suppositories arefilled each containing 25 mg. of active substance.

(h) 8 g. of 1-(3-phenylpropyl)-4-allyl isonipecotic acid morpholidehydrochloride and 2.2 g. of glycerin are dissolved in distilled water togive 100 ml., and from the solution are filled 100 ampoules each of 1ml. and each containing 20 mg. of active substance.

The following examples illustrate the production of the new compounds ofthe Formula I but they in no way limit the scope of the invention.Temperatures are given in degrees centigrade.

EXAMPLE 1 6.3 g. of 1-(3-phenylpropyl)-4-allyl isonipecotic acid ethylester are refluxed in 20 ml. of 20% potassium hydroxide solution and 30ml. of ethanol are refluxed for 8 hours. The reaction solution is thenmade acidic With concentrated hydrochloric acid and concentrated byevaporation. The residue, as far as possible, is dissolved in methylenechloride. The solution is filtered and concentrated by evaporation,whereby the crude hydrochloride of the 1-(3-phenylpropyl)-4-allylisonipecotic acid remains behind.

The above acid hydrochloride is again dissolved in 40 ml. of methylenechloride and a mixture of 30 ml. of oxalyl chloride and 20 m1. methylenechloride is added while stirring within 15 minutes at room temperature.The reaction mixture is then stirred for a further 30 minutes and thenconcentrated by evaporation in vacuo at 30, whereby the1-(3-phenylpropyl)-4-allyl isonipecotoyl chloride hydrochloridecrystallises out.

The obtained crude acid chloride hydrochloride is dissolved in 50 m1. ofmethylene chloride. While stirring and cooling with ice, the mixture of30 ml. of methylamine and 20 ml. of methylene chloride is added dropwiseto this solution within 15 minutes. The reaction mixture is stirred fora further hour and then concentrated by evaporation in vacuo. Theresidue is mixed with 20 ml. of water and extracted with methylenechloride. The methylene chloride solution is dried and evaporated andthe residue mixed with a small excess, relative to the initially usedester, of ethereal hydrogen chloride solution. TheN-methyl-1-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride, whichhas crystallised out, is filtered 01f, M.P. 204-206.

If necessary, the residue of the above methylene chloride extract, whichconsists of crude N-methyl-1-(3-phenylpropyl)4-allyl isonipectoarnide,is purified of salt formation by chromatography on silica gel in amixture of chloroformmethanol of 95:5.

In an analogous manner, using ammonia or the corresponding amines inplace of methylamine, the following amides and their hydrochlorides areproduced:

1- 3-phenylpropyl -4-all=yl isonipecotamide hydrochloride,

N-ethyl-1-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride, M.P.178-179;

N-n-propyl-l-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride,M.P. 178-179;

N-isopropyl-1-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride,M.P. 146-147";

N-n-butyl-1-( 3-phenylpropyl) -4-allyl isonipecotamide hydrochloride,M.P. 175-176";

N,N-dimethyl- 1- 3-phenylpropyl) -4-allyl isonipecotamide hydrochloride,M.P. 140-141";

N-allyl-1-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride, M.P.173l74.

The 1-(3-phenylpropyl)-4-allyl isonipecotic acid ethyl ester, requiredas starting material, is produced as follows: (a) 20 g. of isonipecoticacid ethyl ester are refluxed with 75.5 g. of 3-phenylpropyl bromide in100 ml. of ethanol for 5 hours. The ethanol is then evaporated off undervacuum, the residue dissolved in water and the aqueous solutionextracted three times with ether. With concentration of the aqueoussolution by evaporation in vacuo and finally under high vacuum, theethyl ester of the 4-carboxy-1-(3-phenylpropyl) pyridinium bromideremains behind.

(b) 24.1 g. of the above quaternary salt are hydrogenated in thepresence of rhodium/aluminium oxide catalyst (5% Rh) in 200 ml. ofethanol at room temperature and 3-4 atm. pressure. The catalyst is thenfiltered off and the filtrate concentrated. The residue is covered withchloroform and made alkaline with concentrated sodium hydroxidesolution. The chloroform is removed and the aqueous phase exhaustivelyextracted with chloroform. The combined chloroform solutions are washedwith saturated sodium chloride solution, dried and concentrated and theresidue is distilled under high vacuum. The 1-(3-phenylpropyl)isonipecotic acid ethyl ester boils at 130-132/0.08 torr.

(c) In a 350 ml. four-necked flask, 0.98 g. of lithium wire, cut intosmall pieces and washed with petroleum ether, are added under nitrogento 11.0 g. of bromobenzene in 100 ml. of abs. ether While stirring,whereby the ether commences to boil. After the reaction has subsided,the mixture is refluxed for another 2 /2 hours. 17.1 g. oftriphenylmethane in 80 ml. of abs. 1,2-dimethoxyethane are added all atonce to the obtained solution of phenyl lithium, whereby, due to theformation of triphenylmethyl lithium, the solution assumes a deep redcolour and gently boils. After 20 minutes stirring at room temperature,18.3 g. of 1-(3-phenylpropyl) isonipecotic acid ethyl ester in 20 ml. ofabs. ether are added at 28. Accompanied by a slight increase intemperature, the deep red solution loses its colour. It is stirred forminutes at room temperature and then mixed all at once with 8.45 g. ofallyl bromide in ml. of abs. ether. The mixture is stirred for 2 /2hours at room temperature, whereby it becomes yellowish in colour andlithium bromide precipitates out. The reaction mixture is thendecomposed with 10 ml. of water and concentrated in the rotaryevaporator. Ether is added to the residue and the obtained ethersolution extracted four times with diluted hydrochloric acid. The acidextracts are made alkaline and exhaustively extracted with chloroform,the chloroform extracts being then dried 10 and concentrated. Theresidue is taken up in ether, the ether solution dried and concentratedand the residue distilled. The l-(3-phenylpropyl)-4-allyl isonipecoticacid ethyl ester boils at 178/ 0.01 torr, fumarate M.P. 138 (fromisopropanol) EXAMPLE 2 6.3 g. of 1-(3-phenylpropyl)-4-allyl isonipecoticacid ethyl ester (see Example 1(a), (b) and (c)) are converted accordingto the two first paragraphs of Example 1, into the crude acid chloridehydrochloride. This is dissolved in 50 ml. of methylene chloride and,while stirring and cooling with ice, 25 ml. of morpholine in 50 ml. ofmethylene chloride are added dropwise to the obtained solution within aperiod of 15 minutes. The reaction mixture is then stirred for anotherhour and then concentrated in vacuo. The residue is mixed with 40 ml. ofwater and extracted with methylene chloride. The methylene chloridesolution is dried and concentrated by evaporation and the residue mixedwith a small excess of ethereal hydrogen chloride solution. The formedl-(3-phenylpropyl)-4- allyl isonipecotic acid morpholide hydrochlorideis filtered off and optionally recrystallised from acetone ether, M.P.184-185 The following are obtained in an analogous manner:

1-(3-phenylpropyl)-4-allyl isonipecotic acid pyrrolidide hydrochloride,M.P. 173-174";

1-(3-phenylpropyl)-4-allyl isonipecotic acid piperidide hydrochloride,M.P. 123-124".

EXAMPLE 3 6.0 g. of 1-(3-phenylpropyl)-4-(2-propinyl)-isonipecotic acidethyl ester (see below) are converted, analogously to the firstparagraph of Example 1, into the crude hydrochloride of thecorresponding acid. This is dissolved in 40 ml. of methylene chlorideand a mixture of 25 ml. of oxalyl chloride and 5 0 ml. of methylenechloride is added dropwise while stirring within 15 minutes at roomtemperature. After a further 30 minutes stirring, the reaction mixtureis concentrated in vacuo at 30, whereby the 1-(3- phenylpropyl)-4-(2-propinyl) isonicotinoylchloride hydrochloride remains behind.

The obtained acid chloride hydrochloride is dissolved in 50 ml. ofmethylene chloride and, while stirring and cooling with ice, 25 ml. ofmorpholine in 50 ml. of methylene chloride are added dropwise within 15minutes to the obtained solution. The reaction mixture is then stirredfor another hour and then concentrated in vacuo. The residue is mixedwith 40 ml. of water and extracted with methylene chloride. Themethylene chloride solution is dried and concentrated and the residuemixed with a small excess of ethereal hydrogen chloride solution. Theformed 1-(3- phenylpropyl)-4-(2-propinyl) isonipecotic acid morpholidehydrochloride is filtered off and recrystallised from methylene chlorideacetone ether, M.P. 186-187".

Analogously, the following are obtained using methylamine ordimethylamine in place of morpholine:

Nmethyl-i1-(3-phenylpropyl)-4-(2 propinyl) isonipecotamidehydrochloride, M.P. 203-204";

N,N-dimethyl-l-(3-phenylpropyD-4 (2 propinyl) isonipecotamidehydrochloride, M.P. 179-181.

The '1-(3-phenylpropyl)-4-(2-propinyl)isonipecotic acid ethyl ester,B.P. -l72/0.05 torr, fumarate M.P. 153 (from isopropanol) is producedanalogously to Example 1(a), (b) and (0), whereby in the case of (c),the same quantity of propargyl bromide (3bromopropine) is used in placeof allyl bromide.

EXAMPLE 4 15 g. of '1-(3-phenylpropyl)-4-allyl-isonipecotic acid ethylester with 5 0 ml. of 20% potassium hydroxide solution and 70 ml. ofalcohol are refluxed for 8 hours. The mixture is then concentrated byevaporation in vacuo and the excess potassium hydroxide solutionneutralised with 2 N hydrochloric acid and concentrated to dryness. 7.65g. of the above mentioned mixture of the salt of the isonipecotic acidand sodium chloride are suspended in 50 ml. of toluene and to this areadded 6.45 g. of dimethylcarbamyl chloride in 50 ml. of toluene within 5minutes. The mixture is then slowly heated, whereby the evolution of gasat 90 is observed. The mixture is refluxed for a further 30 minutes,concentrated in vacuum, the residue boiled with ether, dried andevaporated. The hydrochlride is produced in the usual manner from theoil which remains. The 1-(3-phenylpropyl)-4-allyl-isonipecotic aciddimethyl amide hydrochloride melts at 140-141".

EXAMPLE 1 g. of 4-allyl-isonipecotic acid ethyl ester with 6 ml. of 20%potassium hydroxide solution and 6 ml. of ethanol are refluxed for 6hours. The mixture is then concentrated to dryness in vacuo and themoisture removed by repeated distilling with benzene. The residue isthen taken up in 10 ml. of methylene chloride and mixed with a solutionof ml. of oxalyl chloride in 15 ml. of methylene chloride, whereupon themixture is reacted for 15 mnutes. The excess oxalyl chloride and themethylene chloride are evaporated at room temperature. The mixture isthen evaporated once with benzene in vacuo and the residue is againdissolved in 10 ml. of methylene chloride. To this solution is added asolution of 10 ml. of morpholine in 15 ml. of methylene chloride. Themixture is stirred for 15 minutes and evaporated in vacuo. The residueis taken up in a little water, a little concentrated ammonia is addedand the residue is extracted three times with methylene chloride. Themethylene chloride is dried and evaporated, whereby the4-allyl-isonipecotic acid morpholide remains. This residue is taken upin 10 ml. of diethyl ketone and refluxed for 12 hours with 5 ml. of 3-phenyl-propyl chloride and 0.5 g. of potash (potassium carbonate). Themixture is subsequently filtered, the filtrate concentrated byevaporation and the oil which remains is chromatographed on silica gelin chloroform/ methanol 95:5. The 1-(3-phenylpropyl)-4-allylisonipecoticacid morpholide hydrochloride is produced with ethereal hydrochloricacid and recrystallised from acetoneether. It has a melting point of184-185.

The following amides and their hydrochlorides are produced in ananalogous manner:

1-(3-phenylpropyD-4-allyl isonipecotamide hydrochloride, M.P. 214-215;

N-ethyl-1-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride, M.P.178179;

N-n-propyl-1-(3-phenylpropy1)-4-allyl isonipecotamide hydrochloride,M.P. 178-179";

N-isopropyl-1-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride,M.P. 146-147";

N-n-butyl-l-(3-phenylpropyl)-4-allyl isonipecotamide hydrochloride, M.P.175-176"; N,N-dimethy1-1-( 3-phenylpropyl) -4-allyl isonipecotamidehydrochloride, M.P. 140-141; N-allyl-1-(3-phenylpropyl)-4-ally1isonipecotamide hydrochloride, M.P. 173174.

12 What we claim is: 1. A pharmaceutical composition comprising (a) anantitussive effective amount of a compound of the formula wherein R isphenylalkyl having at most 9 carbon atoms,

R is allyl or propinyl, and

R and R are, independently of each other, hydrogen,

lower alkyl or lower alkenyl, or

R and R are, together with the adjacent nitrogen atom,polymethyleneimino having from 5 to 7 ring members, or morpholino,

or pharmaceutically acceptable acid addition salts thereof, and

(b) an inert pharmaceutical carrier.

2. The method of producing an antitussive effect in a mammal, comprisingadministering to said mammal in need thereof an antitussive effectiveamount of a com pound according to claim 1.

3. A composition as claimed in claim 1, wherein R is 3-pheny1propyl,

R is allyl,

R is hydrogen, and

R is methyl.

4. A composition as claimed in claim 1, wherein R is 3-phenylpropyl,

R is allyl,

[R is hydrogen, and

R is isopropyl.

5. A composition as claimed in claim 1, wherein R is 3-phenylpropyl,

R is allyl, and

R and R together with the adjacent nitrogen atom is morpholino.

6. A composition as claimed in claim 1, wherein R is 3-phenylpropyl,

R is 2-propinyl, and

R and R together with the adjacent nitrogen atom is morpholino.

References Cited FOREIGN PATENTS 602,228 3/1961 Belgium.

4,176 3/ 1968 South Africa.

ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Assistant Examiner US.Cl. X.R. 424267

